Abstract: The lack of data to inform treatment guidelines in patients with severe asthma remains a major unmet need. Our vision is to develop a personalized medicine approach for the treatment of severe asthma, directed at its pathogenesis and ultimately translatable to the community health care setting for implementation. Because traditional clinical trial designs are inefficient for diseases with multiple phenotypes, our central hypothesis is that the application of an adaptive trial design will identify subtypes of severe asthma that will be most responsive to precise interventions. The scientific rationale for this proposal includes recent data showing that elevated blood eosinophils, maximum FEV1 reversal, and plasma IL-6 concentrations are risk factors for frequent exacerbations which are a major component of severe asthma. Each of these phenotypes has precise interventions that are FDA approved for asthma or other diseases, namely anti-IL-5 antibodies, long acting muscarinic antagonists, and anti-IL6 receptor antibodies. We propose the following Specific Aims to test this hypothesis: 1) To determine the impact of phenotype-directed interventions on the frequency of asthma exacerbations using a sequential Bayesian adaptive clinical trial design, stratified by blood eosinophils, maximum FEV1 reversal, and plasma IL-6 concentrations; and 2) To validate the predictive value of monitoring biomarkers assessed at baseline and after three months of treatment. These biomarkers include sputum eosinophils, heart rate variability, C-reactive protein levels, air trapping and other imaging metrics assessed by low dose chest CT scan, and measures of airway oxidant stress. Our team of multi-disciplinary investigators and translational science clinicians in the Great Lakes PrecISE Partnership has access to a diverse population of patients with severe asthma from Wisconsin and Northern Illinois which will enable us to be a very active partner in this collaborative network. We expect to rapidly identify patient subsets that benefit from therapies not currently considered as part of the asthma pharmacopoeia. The efficient assessment of these biomarkers and precise treatments would not be possible without this departure from the typical therapeutic development process.